Alkyl esters of 4-substituted phenoxyisobutyric acid

ABSTRACT

ALKYL ESTERS OF 4-SUBSTITUTED PHENOXYISOBUTYRIC ACID WHICH ARE USEFUL IN THE TREATMENT OF HYPOCHOLESTEROLEMIA IN MAMMALS AND AS PREVENTIVES OF BILIARY LITHIASIS IN MAMMALS.

United States Patent 3,632,629 ALKYL EsTEns or astmsrrrurnn rrrnraoxrrsonorrme ACID Gerard Bulteau, Paris, France, assignor to Socit rm. Cl. civic 69/76 U.S. Cl. 260-470 Claims ABSCT OF THE DISCLOSURE alkyl esters of 4-substituted phenoxyisobutyric acid whlch are useful in the treatment of hypocholesterolemia to mammals and as preventives of biliary lithiasis in mammals.

This invention relates to esters of isobutyric phenoxy acid derlvatives and more particularly to fluorine derivatlves of isobutyric esters having the formula:

in which R is an alkyl radical of 1 to 5 carbon atoms either straight or branched chained; X is a trifluoromethyl, trifiuoromethylthio, trifluoromethylsulfinyl or trifluoromethylsulfonyl.

The compositions of this invention are effective in the treatment of mammals aflfected with hypocholesterolemia and as preventives of biliary lithiasis in mammals.

In accordance with this invention, the process of preparation of these compounds consists in starting with a substituted phenol in combination with a radical such as trifluoromethyl, trifluoromethylthio, trifluoromethylsulfinyl, trifluoromethylsulfonyl; treating it with chloroform and acetone in the presence of potash so as to obtain the corresponding isobutyric phenoxy acid. This is then esteri-fied by an alcohol of low molecular weight such as methanol, ethanol, propanol, isopropanol, etc. in the presence of a catalyzing agent. The ethyl esters are particularly effective because of their high cholesterol control properties.

The preparation of the following compositions is given as an example, without limiting the invention.

EXAMPLE I Ethyl-p-trifluoromethylphenoxyisobutyrate Stage A.p-Nitrotribromotoluene: Into a 1 liter threeuecked flask equipped with a mechanical agitator, an as cendant refrigerant and a dropping funnel, there are introduced 137 g. (1 mole) of p-nitrotoluene. The bromine is poured slowly into the flask heated to 195200 C. When the introduction of the bromine is completed, the mixture is allowed to return to room temperature and the product is extracted with petroleum ether. The product is then treated with a solution of sodium hypobromide for 48 hours. When the reaction is completed, the product is dried, washed with water and recovered with methanol. 112 g. of p-nitrotribromotoluene are obtained. (Yield: 30%, M.P.: 86 C.)

spam Patented Jan. 4, 1972 "ice Stage B.p-Trifluoromethylnitrobenzene: Into a 1 liter flask equipped with a small distillation column joined to a descendant refrigerant, 112 g. (0.3 mole) of p-nitrotribromotoluene and g. of pulverized antimony trifiuoride are introduced. The flask is heated. When the highly exothermic reaction is completed, the product is distilled and is then extracted with ethyl ether. 40 g. of p-trifluoromethylnitrobenzene are obtained. (Yield: 70%, M.P.: 40 C.)

Stage C.p-Trifluoromethylaniline: Into a 1 liter threenecked flask equipped with a mechanical agitator, a thermometer and a dropping funnel are introduced 40 g. of p-trifluoromethylnitrobenzene (0.2 mole) and 120 ml. of absolute ethanol. There is then poured in under agitation a solution of 240 g. of stannous chloride in 200 ml. of hydrochloric acid ((1: 1.19). When the reduction is completed, the mixture is neutralized with soda lye (36 B.) and recovered several times with ether, then washed in water, dried with sodium anhydrous sulfate, and then distilled. 32 g. of p-trifluoromethylaniline are obtained. (Yield: about 100%, M.P. 32 C.)

Stage D.p-Trifluoromethylphenol: Into a 1 liter threenecked flask equipped with a mechanical agitator, a thermometer and a dropping funnel there are introduced 180 ml. of water and then 27 ml. of sulfuric acid (d: 1.84). With the temperature maintained at about 20 C., 32 g. (0.2 mole) of p-trifluoromethylaniline are poured in slowly, and then drop by drop, a solution of 15 g. of sodium nitrite in 70 ml. of Water. The mixture is maintained under agitation at room temperature for about one hour. The product formed is steam distilled and then recovered several times in ether. The ether is dried and distilled. 27.5 g. of p-trifiuoromethylphenol are obtained. (Yield:

Stage E.-p-Trifiuoromethylphenoxyisobutyric acid: Into a 1 liter three-necked flask equipped with a mechanical agitator, an ascendant refrigerant and a dropping funnel there are introduced 27.5 g. (0.17 mole) of p-trifluoromethylphenol, 105 g. of acetone and 37 g. of pellets of soda. The mixture is refluxed and 25 g. of chloroform are poured slowly through the dropping funnel. When the reaction is completed, the acetone is removed under vacuum and the residue recovered in water and the pH is raised to 1 with concentrated hydrochloric acid. The product obtained is extracted in chloroform. 21 g. of p-trifluoromethylphenoxyisobutyric acid are obtained. (Yield: 50%, M.P.: C.)

Stage F.Ethyl p-trifluoromethylphenoxyisobutyrater Into a 500 ml. liter flask equipped with an ascendant refrigerant there are introduced 21 g. (0.085 mole) of p-trifluoromethylphenoxyisobutyric acid and a mixture of ml. of absolute ethanol and 4 g. of concentrated sulfuric acid of 66 B. The mixture is refluxed for 5 hours. It is extracted in chloroform, the solvent removed and the residue distilled. 13.8 g. of ethyl p-trifluoromethylphenoxyisobutyrate are obtained. (Yield: 60%, boiling at 2 to 3 'mm.: 91-94" C.)

EXAMPLE II Ethyl p-trifluorornethylthiophenoxyisobutyrate Stage A.p-Nitrophenylmethylsulphidez Into a 5 liter flask equipped with a mechanical agitator, an ascendant refrigerant and a dropping funnel there are introduced 315 g. (2 moles) of p-chloronitrobenzene and 1500 ml. of 95% ethyl alcohol. The mixture is refluxed with agitation. As the reflux is continued, there is added in a thin stream a solution of 350 g. of sodium sulfide-9H O, 50 g. of sulphur and 2000 ml. of 95% alcohol.

Reflux is continued for /2 hour and then a solution of soda pellets in ml. of Water and 500 ml. of 95% alcohol is poured into the reaction mixture.

The reaction product is poured into a mixture of ice and water. The impurities are eliminated by filtration. The filtrate is acidified with hydrochloric acid (d:1:15). The clear yellow precipitate obtained is dried and washed with water. It is then dissolved in 200 ml. of soda lye (36 B.) and 2000 ml. of water and poured into a 5 liter flask equipped with a mechanical agitator, an ascendant refrigerant and a dropping funnel. Then under agitation, 380 g. of dimethyl sulfate are added. The mixture is refluxed for 1 hour, being assured that the medium is alkaline. The mixture is then allowed to return to room temperature. The product crystallizes, is dried, washed with water and dried at 50 C. After recrystallization in methanol, 16 g. of p-nitrophenylmethylsulphide are obtained. (Yield: 50%, M.P.: 71-72 C.)

Stage B.p-nitrophenyltrichloromethylsulphide: Into a 1 liter three-necked flask 169 g. (1 mole) of p-nitrophenylmethylsulphide are introduced and dissolved by heating in 620 ml. of chloroform. A part of the chloroform is then distilled and a stream of chlorine passed into the flask, the reaction temperature being maintained between and C. The reaction being photo sensitive, it is catalyzed by a luminous flux. The reaction is completed in 4 hours. The chloroform is distilled and the product recrystallized in acetone. 218 g. of p-nitrophenyltrichloromethylsulfide are obtained. (Yield: 80%, M.P. 94 C.)

Stage C.p-Nitrophenyltrifluoromethylsulphide: Into a 1 liter flask equipped with a small distillation column and a descendant refrigerant, are introduced 218 g. (0.8 mole) of p-nitrophenyltrichloromethylsulphide and 218 g. of i pulverized antimony trifluoride. The mixture of the two compositions is brought rapidly to the boiling point. It is then distilled under vacuum. The product obtained is recovered in 900 ml. of sulfuric ether and 90 ml. of hydrochloric acid (d: 1.19) diluted /2. The etherified layer is 1 decanted and recovered several times by washing in /2 hydrochloric acid. The ether is dried in anhydrous sodium sulphate and then distilled. The product is then distilled. 112.4 g. of p-nitrophenyltrifluoromethylsulfide are obtained. (Yield: boiling at 9 mm.: 99103 C.)

Stage D.-p-aminophenyltrifluoromethylsulfide: Into a 6 liter three-necked flask equipped with a mechanical agitator, a thermometer and a dropping funnel, are introduced 112.4 g. (0.5 mole) of p-nitrophenyltrifluoromethylsulfide and 400 ml. of 95% ethyl alcohol. Reduction is effected with a solution of 650 g. of stannous chloride in 490 ml. of hydrochloric acid (d: 1.19). After neutralization in soda, the product is extracted several times in ether, which is washed in water, dried in anhydrous sodiurn sulfate and then distilled. The product is then distilled. g. of p-aminophenyltrifluoromethylsulphide are obtained. (Yield: 83%, boiling at 10 mm.: 9899 C.)

Stage E.p Hydroxyphenyltrifluoromethylsulphide: Into a 2 liter three-necked flask equipped with a mechanical agitator, a thermometer and a dropping funnel, there are introduced 450 ml. of water and then 100 ml. of pure sulfuric acid (d: 1.84). With the temperature being maintained at 20 C., 80 g. of p-aminophenyltrifluoromethylsulphide are poured in, in a thin stream, and then, drop by drop, a solution of 40 g. of sodium nitrite in 180 ml. of water. The mixture is maintained under agitation at room temperature for about 1 hour. The product formed is drawn off by steam and the product is recovered several times in ether. The ether is dried and distilled. 68.5 g. of p-hydroxyphenyltrifluoromethylsulphide are obtained. (Yield: M.P.: 52 C., boiling at 10 mm.: C.)

Stage F.p-Trifluoromethylthiophenoxyisbutyric acid: Into a 1 liter three-necked flask, equipped with a mechanical agitator, a reflux refrigerant and a dropping funnel, there are introduced 260 g. of acetone, 68.5 g. of p-trifluoromethylthiophenol and 100 g. of soda pellets. The mixture is refluxed and 70 g. of chloroform are poured slowly into the dropping funnel. When the reaction is complete, the acetone is removed under vacuum and the residue recovered in water, then brought to a pH of 1 with concentrated hydrochloric acid. The product oh tained is extracted with chloroform. 69 g. of p-trifluoromethylthiophenoxyisobutyric acid are obtained. (Yield: 70%, M.P.: 118 C.)

Stage G.--Ethyl p-trifluoromethylthiophenoxyisobutyrate: Into a 500 ml. flask equipped with an ascendant refrigerant, are introduced 69 g. of p-trifluoromethylthiophenoxyisobutyric acid and a mixture of 280 ml. of absolute ethyl alcohol and 12 g. of sulfuric acid of 66 B. The mixture was refluxed for 6 hours. The mixture was extracted with chloroform, the solvent removed and the residue distilled. 49 g. of ethyl p-trifluoromethylthiophenoxyisobutyrate are obtained. (Yield: 65%, boiling at 5 mm.: 114 C.)

EXAMPLE III Ethyl p-trifluoromethylsulfinylphenoxyisobutyrate Stages A through F are the same as those described in Example 11.

Stage G.-p-Trifluoromethylsulfinylphenoxyisobutyric acid: Into a 2 liter three-necked flask, equipped with a mechanical agitator, a thermometer and a dropping funnel, are introduced 800 ml. of methanol, a solution of 40 g. of sodium metaperiodate in 370 ml. of water and finally 50 g. (0.178 mole) of p-trifluoromethylthiophenoxyisobutyric acid. The mixture is maintained under agitation at room temperature for 4 /2 hours. When the reaction is completed, the product, having been recovered several times in chloroform, is extracted. 44 g. of p-trifluoromethylsulfinylphenoxyisobutyric acid are obtained. (Yield: 83%, M.P. 123 C.)

Stage H.Ethyl p-trifluoromethylsulfinylphenoxyisobutyrate: The esterification of p-trifluoromethylsulfinylphenoxyisobutyric acid is effected as described in Example II, stage G. The corresponding ester is obtained. (Yield: 58%, boiling at 5 mm: 122-124 C.)

EXAMPLE IV Ethyl p-trifluoromethylsulfonylphenoxyisobutyrate Stages A through F are the same as those described in Example II.

Stage G. p-trifluoromethylsulfonylphenoxyisobutyric acid: Into a 1 liter three-necked flask equipped with a mechanical agitator and an ascendant refrigerant, are

introduced 58 g. of p-trifluoromethylthiophenoxyisobutyric acid dissolved in 300 ml. of acetic acid and 125 ml. of hydrogen peroxide in volumes. When the reaction is completed, the acetic acid is dissolved under vacuum. The crystallized product at the bottom of the flask is recovered by water, dried, washed several times with water, then dried at 50 C. 55 g. of p-trifluoromethylsulfonylphenoxyisobutyric acid are obtained. (Yield: 85%, M.P.: 101 C.)

Stage l-I.Ethyl p-trifluoromethylsulfonylphenoxyisobutyrate: The esterification of p-trifluoromethylsulfonylphenoxyisobutyric acid is eflected as illustrated in EX- ample II, stage G. Ethyl p-trifluoromethylsulfonylphenoxyisobutyrate is obtained. (Yield: 61%, boiling at 5 mm.: 149-152 C.)

The compositions of this invention have been the subject of pharmacological and clinical studies to determine both their non-toxicity, their activity in reducing hypocholesterol and in preventing biliary lithiasis.

The toxicity tests of the medicaments of this invention carried out on mice weighing an average of 22 g. showed perfect tolerance of doses up to mg. per mouse (V10 The pharmacological studies of the medicaments of the invention showed significant protection against lithiasis of the gall bladder as well as protection against hypocholesterol.

6 The preventive action in lithiasis of the gall bladder doubly refractive crystals of small size and a maximum was studied in accordance with the test of Francois of 2 or 3 larger crystals in the gall bladder content. Besancon and Coll. described in Socit Mdicale des On the other hand, in the animals treated by the Hopitaux de Paris 1966, 117, No. 2, 127-138. lithogenous regime supplemented by the medications of Four lots of five female mice three months old, of this invention, no lithiasis was observed. Only 2 mice Swiss-Git breed were tested by lithogenous regime for 5 showed small crystals under microscopic examination, but six weeks. The lithogenous regime is a normal nourishin greater than normal numbers. ment for mice supplied by the UAR. Establishments, The other mice were normal under microscopic exwith the addition of 0.5% dosage of sodium dehydroamination. Thus the significant efficacy of the medicachlorate (cf. Francois Besangon and C011. 1965-1966). ments of this invention against gall bladder lithiasis is The lot tested received no other treatment. One of the shown experimentally. medicaments of the invention was administered to each The hypocholesterol control activity of the composiof 3 other lots subcutaneously in dosages of 36 mg., 6 tions of this invention were studied according to the days per week for 6 weeks. technique of Thorp and Waring (Nature 1962, 194,

At the end of the treatment, the mice were sacrificed and 948-49) as described hereafter. autopsies performed on them. The weight of the animals, The animals (male rats Wistar) received orally a comthe weight and color of their livers, the dimensions of bination of androsterone and the medication under study the gall bladder, the presence of macroscopically visible incorporated in the diet in rates of 0.01% and 0.25% stones and observations by polarizing microscope were respectively for 11 days. noted. The findings are given in the following table.

TABLE I Vesicle Weight 01- Percent weight Color Dimen- Mouse Liver of of Lithisions,

in g. in g. liver liver asis mm. Birefringent crystals 1.68 6.6 Colorless 7X3 Numerous largemasses. 28 1.67 6 Nonnal O 5.5X2.5 Normal. 28 1.38 4.9 do 6X3 Many large masses. 2 5.7 do 6.5)(3 Normal. 25 1.04 4.2 .do 7.5)(3 Many large masses normal.

30 3.25 11 do 0 exaa Normal. 20 2.60 13 do O 4x1 Do. 30 2.30 7 7 ..do 0 6X3 Do.

22 3.85 18 ..do 0 6X2 Small N0. of large masses many small masses. 20 3.50 18 do.. O 11X2 Normal. 24 3.60 15 ..do O 5X1.5 Numerous very small masses.

25 4.80 19 do 0 exas Do. 21 3.92 19 Colorless O 7.5)(4 Normal. 20 3.70 19 Normal...() 7X2 D0.

No'rE: Compound I=ethyl p-trifluorornethylsulfonylphenoxylsobutyrate; Compound II=ethyl p-trifluoromethylthiophenoxyisobutyrate; Compound IIl=ethyl p-trifiuoromethylphenoxyisobutyrate.

Table I demonstrates that in the five test mice sub- At the conclusion of the experiment, the rats were jected to the lithogenous regime with no other treatment, sacrificed in parts of the carotides and the cholesterol was four showed macroscopically visible lithiasis and the given in doses to each animal by the method of Bloor. polarizing microscope showed large cohesive doubly re- The results for three of the compositions of this invention are given in the following table.

TABLE 11 Average weight in g. Daily intake 0i Cholester- No. of Before After Gain, nourishment olemia, Treatment aminals testing testing percent in g. g./l

0 5 162 226 39 87 0.92 Androsterone 5 187 219 33 97 0 90 Androsterone plus Compound L 2 4 186 270 45 89 0. 76 Androsterone plus Compound II- 5 151 198 31 85 0. 63 Androsterone plus Compound IIL 5 168 208 23 83 0. 61

2 One animal losing weight because of a microbial infection was eliminated.

fractive crystals. In the fifth mouse, microscope study The comparison of the cholesterolemias of the animals showed normal bile and absence of lithiasis. The normal treated with androsterone or in combination with comaspect of the bile is demonstrated by the existence of few pounds of the invention was made by comparative analysis.

The results show a highly significant hypocholesterolemia action by three of the compounds of this invention.

The pharmacological results were confirmed in human therapy, the compositions being administered in the form of capsules in dosages ranging from 1 to 2 grams per day.

What is claimed is: 1. A fluorinated derivative of a phenoxy isobutyric acid having the formula:

100R CH -(f-C'H I in which R is a straight or branched chained alkyl having 1 through 5 carbon atoms and X is a trifluoromethyl, trifluoromethylthio, trifluoromethylsulfinyl or trifiuoromethylsulfonyl.

2. A compound of claim 1 which is ethyl p-trifluoromethylphenoxyisobutyrate.

3. A compound of claim 1 which is ethyl p-trifluoromethylthiophenoXy-butyrate.

4. A compound of claim 1 which is ethyl p-trifluoromethylsulfinylphenoxyisobutyrate.

5. A compound of claim 1 which is ethyl p-tr-ifluoromethylsulfonylphenoxyisobutyrate.

References Cited FOREIGN PATENTS 1,133,902 11/1968 England 260473 US. Cl. X.R.

260473 G, 516, 521 A, 580, 623, 609 E, 645; 424-308 

